According to principal investigator Jingsong Zhang, M.D., Ph.D., an assistant member of the Chemical Biology and Molecular Medicine Program at Moffitt, more than 90 percent of patients with end-stage prostate cancer have disease that has spread to the bone. The U.S. Food and Drug Administration-approved bone targeted therapies zoledronic acid (Zometa) and denosumab (Xgeva) prevent or delay the complications of bone metastasis, but have not been shown to prolong the life of prostate cancer patients.

Despite the approval of newer agents like abiraterone (Zytiga) and enzalutamide (Xtandi), not all patients respond, and even for responders these treatments are not curative. There is an urgent need to develop more effective treatments for metastatic castration-resistant prostate cancer.

Researchers know that two growth factors, hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF), play a big role in advanced prostate cancer, especially in cases of castration-resistant prostate cancer. MET is a transforming cancer-related gene that encodes the HGF receptor. The gene is activated in cancer and researchers have found that MET is highly elevated in tumor samples from patients with metastatic prostate cancer, as compared to samples from prostate cancer patients who did not undergo androgen-deprivation therapy. HGF and MET are also involved in the processes that lead to bone metastases.

“Cabozantinib is a tyrosine kinase inhibitor with good activities against MET and VEGF receptor 2,” Zhang explained. “Cabozantinib suppresses MET and VEGF2 signaling. Inhibiting both can lead to the death of tumor cells.”

The FDA recently approved cabozantinib for the treatment of thyroid cancer. In the recently reported phase II study for advanced prostate cancer with cabozantinib, 68 percent of patients showed bone scan improvements and 72 percent experienced regression in soft tumor lesions, as well as longer documented progression-free survival. There was also strong evidence among phase II patients for new bone formation, bone pain reduction (67 percent), a concomitant reduction in narcotics need (56 percent), and a subsequent improvement in quality of life. Based on these impressive phase II results, Exelixis, the manufacturer of cabozantinib, recently launched this randomized, double-blind, phase III study. The participants in this phase III trial will be men with metastatic castration-resistant prostate cancer that has metastasized to the bone and who have failed standard treatments, including androgen-deprivation therapy, chemotherapy, abiraterone and enzalutamide

The goal of the trial is to prolong the life of these men with cabozantinib.

The multicenter, international, phase III trial began in June and is anticipated to be complete in March 2014.